: Theiler's murine encephalomyelitis virus (TMBV) infection of mice is a relevant animal model for the human demyelinating disease multiple sclerosis (MS). TMEV belongs to the Picornaviridae family and are in the Cardiovirus genus. These viruses are small positive-sense single-stranded RNA viruses. Infection of mice with the DA strain of TMEV causes an acute polioencephalomyelitis where mice survive and later develop a central nervous system (CNS) inflammatory demyelinating disease. Once clinical signs (weight loss, spastic paralysis and gait disturbances) develop in these mice, there is disease progression without relapses or remissions. This mirrors the progressive forms of MS. Many reports have described the need for CD8+ and CD4+ T cells as well as antibodies in the pathogenesis of TMEV induced demyelinating disease. CD8+ T cells have been reported to be responsible for viral clearance and protection from the chronic demyelinating disease in resistant mice. Similarly, CD4+ T cells have been described to be responsible for the inflammatory CNS demyelination in infected susceptible mice. Recently, CD8+ T cells have also been shown to influence demyelination in DA virus infected mice. We have evidence that another cell type may also participate in TMEV infection and demyelinating disease. This new cell type has cytotoxic activity on uninfected syngenic target cells but not allogenic target cells. In preliminary studies, the cell is CD3+, CD8+ and B22O+ and can cause inflammation in the CNS. These cells are induced by TMEV infection but not vaccinia virus infection of susceptible SJL/J. The goals of this application are to: 1) further characterize the phenotype of the autoreactive killer cells; 2) determine how these cells contribute to disease and define the mechanism of killing; 3) study the induction of the killer cells; and 4) define the determinant(s) in VP1 necessary for the induction of the autoreactive cells. These findings are novel and may help explain differences between various reports stating that CD4+ or CD8+ T cells are exclusively involved in demyelination and viral clearance, respectively. The studies not only are important to viral pathogenesis but also the pathogenesis of autoimmune disease.